OBJECTIVE To evaluate the effectiveness of olanzapine versus aripiprazole in patients with schizophrenia. METHOD Patients aged 18 to 65 years with schizophrenia (diagnosed according to DSM-IV-TR criteria) were randomly assigned to either olanzapine (n = 281) or aripiprazole (n = 285) for 28 weeks of double-blind treatment. The primary outcome was time to all-cause discontinuation. Efficacy was measured by Positive and Negative Syndrome Scale (PANSS) total change from baseline. Time-to-event data were analyzed via the Kaplan-Meier method. The study was conducted from October 2003 to July 2007. RESULTS Treatment groups did not differ significantly in time to all-cause discontinuation (p = .067) or all-cause discontinuation rate (olanzapine, 42.7% vs. aripiprazole, 50.2%; p = .053). Olanzapine-treated patients had significantly longer time to efficacy-related discontinuation (p or= 7% body weight gain at any time (40.3% vs. 16.4%; p or= 126 mg/dL at any time was 1.7% for olanzapine and 0.6% for aripiprazole (p = .623). Fasting mean total cholesterol change was +4.09 mg/dL for olanzapine and -9.85 mg/dL for aripiprazole (p or= 240 mg/dL at any time was 9.2% for olanzapine and 1.5% for aripiprazole (p = .008). Fasting mean triglycerides change was +25.66 mg/dL for olanzapine and -17.52 mg/dL for aripiprazole (p < .001). Treatment groups did not significantly differ on measures of extrapyramidal symptoms. CONCLUSION Treatment groups did not differ significantly on the primary outcome. Olanzapine-treated patients had significantly greater improvement in symptom efficacy at 28 weeks as well as significantly greater mean increases in weight and glucose and significantly greater worsening on lipids parameters. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00088049.